Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy (original) (raw)
Related papers
Journal of Biological Chemistry, 2000
Familial Alzheimer's disease (FAD) is frequently associated with mutations in the presenilin-1 (PS1) gene. Almost all PS1-associated FAD mutations reported so far are exchanges of single conserved amino acids and cause the increased production of the highly amyloidogenic 42-residue amyloid -peptide A42. Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 ⌬I83/⌬M84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic A-positive "cotton wool" plaques in brain parenchyma. Cerebral amyloid angiopathy due to A deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of A42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 ⌬I83/⌬M84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid -peptide A42. Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 ⌬I83/⌬M84 in Notch signaling. Our data therefore demonstrate that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of -amyloid precursor protein and in Notch signaling. Therefore, the PS1 ⌬I83/⌬M84 deletion shows a very similar biochemical/functional phenotype like all other FAD-associated PS1 or PS2 point mutations. Since increased A42 production is not associated with classical senile plaque formation, these data demonstrate that amyloid plaque formation is not a prerequisite for dementia and neurodegeneration.
Journal of the Neurological Sciences, 1998
Missense mutations in the presenilin-1 (PS-1) gene are causally related to the majority of familial early-onset Alzheimer's disease (FAD). PS-1 immunohistochemical expression in normal human brain and in brains with Alzheimer's disease (AD) has so far been controversial. Here, we report a study of PS-1 expression in brains, cell lines and peripheral blood mononuclear cells using a panel of well characterized PS-1-specific antibodies. These antibodies were characterized by immunofluorescent staining of PS-1 transfectants followed by flow cytometric analysis. In human brain, widespread neuronal staining was observed. PS-1 immunoreactivity was primarily confined to neuronal cell bodies and proximal dendrites. Weaker staining of microglia was also detected, in accord with the finding of PS-1 immunoreactivity in monocytes. PS-1 expression is not particularly associated with neurons either containing or spared from neurofibrillary tangles, nor with senile plaques. The level of PS-1 expression does not differ between normal and AD brains. Immunoprecipitation from AD, FAD and control brains revealed only a 32 kDa N-terminal fragment and an 18-20 kDa C-terminal fragment. Little or no full length PS-1 was detected. The enriched presence of PS-1 in neurons implies an important role in neuronal function, however, the lack of apparent association of its expression with AD pathology signifies the need for a better understanding of its pathophysiological role.
Annals of Neurology, 2000
Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep. We studied the serotonergic system in 8 FFI-affected subjects by immunohistochemistry for the serotonin-synthesizing enzyme, tryptophan hydroxylase (TH). Quantification of neurons in median raphe nuclei showed no total neuronal loss in FFI but a substantial increase of TH ؉ neurons (ϳ62%) in FFI subjects compared with controls. Our data indicate an alteration of the serotonergic system that might represent the functional substrate of some typical symptoms of FFI. Wanschitz J, Klöppel S, Jarius C, Birner P, Flicker H, Hainfellner JA, Gambetti P, Guentchev M, Budka H. Alteration of the serotonergic nervous system in fatal familial insomnia. Ann Neurol 2000;48:788 -791
The Journal of Neuroscience
Mutations in the presenilin-1 (PS1) gene is a cause of earlyonset familial Alzheimer's disease (AD). Endogenous PS1 is associated with the endoplasmic reticulum in the cell body of undifferentiated SH-SY5Y neuroblastoma cells. At early stages of neuronal differentiation in rat hippocampal culture, PS1 appears in all neuritic processes and in growth cones. In mature differentiated neurons, PS1 is concentrated in the somatodendritic compartment but is also present at lower levels in axons. A similar localization of PS1 is observed in vivo in neurons of the adult human cerebral cortex. In sporadic AD, PS1 appears in the dystrophic neurites of mature amyloid plaques and colocalizes with a subset of intraneuronal neurofibrillary tangles (NFTs). About 30% of hippocampal NFTs are labeled with a highly specific antibody to the PS1 C-terminal loop domain but not with an antibody to the PS1 N terminus. This observation is consistent with a potential association of the PS1 C-terminal fragment with NFTs, because PS1 is constitutively cleaved to N-and C-terminal fragments in neurons. These results suggest that PS1 is highly expressed and broadly distributed during early stages of neuronal differentiation, consistent with a role for PS1 in neuronal differentiation. Furthermore, the co-localization of PS1 with NFTs and plaque dystrophic neurites implicates a role for PS1 in the diverse pathological manifestations of AD.
Human Mutation, 2006
We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Aβ peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A>C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A>C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Aβ42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Aβ42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype.
Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition
Neurobiology of Aging, 2001
Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral A deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of A40 and A42. A isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of A42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm 2 ) and area (%) of A42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of A40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of A burden in a different fashion from APP717 mutations in their familial AD brains.
Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer’s Disease
Neurotoxicity Research, 2020
Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal factors for early-onset familial AD (FAD). AD pathological features such as memory loss, synaptic dysfunction, and formation of plaques have been successfully mimicked in the transgenic mouse models that coexpress FAD-related presenilin and amyloid precursor protein (APP) variants. γ-Secretase (GS) is an enzyme that plays roles in catalyzing intramembranous APP proteolysis to release pathogenic amyloid beta (Aβ). It has been found that presenilins can play a role as the GS's catalytic subunit. FAD-related mutations in presenilins can modify the site of GS cleavage in a way that can elevate the production of longer and highly fibrillogenic Aβ. Presenilins can interact with β-catenin to generate presenilin complexes. Aforesaid interactions have also been studied to observe the mutational and physiological activities in the catenin signal transduction pathway. Along with APP, GS can catalyze intramembrane proteolysis of various substrates that play a vital role in synaptic function. PSEN mutations can cause FAD with autosomal dominant inheritance and early onset of the disease. In this article, we have reviewed the current progress in the analysis of PSENs and the correlation of PSEN mutations and AD pathogenesis.
Journal of Neuropathology & Experimental Neurology, 2019
In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and a-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and a-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread a-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-b pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and a-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and a-synuclein proteinopathies occur independently or whether a relationship exists between a-synuclein and tau that might explain the mechanisms of coaggregation.
Neurobiology of disease, 2017
Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete ...